Small molecules from antibody pharmacophores (SMAbPs) as a hit identification workflow for immune checkpoints.

ABSTRACT: Small-molecule modulators of immune checkpoints are poised to revolutionize cancer immunotherapy. However, efficient strategies for hit identification are lacking. We introduce small molecules from antibody pharmacophores (SMAbPs), a workflow leveraging cocrystal structures of checkpoints with antibodies to create pharmacophore maps for virtual screening. Applying SMAbPs to five immune checkpoints yielded hits with submicromolar potency in both cell-free and cellular assays. Notably, SMAbPs identified the most potent T cell immunoglobulin and mucin-domain containing-3 and V-domain immunoglobulin suppressor of T cell activation (VISTA) inhibitors reported to date and first-in-class modulators of B and T lymphocyte attenuator, 4-IBB, and CD27. Targeting inhibitory and costimulatory checkpoin

SUBMITTER: Abdel-Rahman SA 

PROVIDER: S-EPMC11482313 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature